Abstract 13955: Small Conductance Ca2+-activated K+ Current is Upregulated via the Phospholylation of CaMKII in Cardiac Hypertrophy
Background: Left ventricular hypertrophy is associated with increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channel is involved in the pathogenesis of ventricular arrhythmias in heart failure. We have recently reported that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased in hypertensive cardiac hypertrophy.
Objective: The aim of this study is to test the hypothesis that SK channels activity is increased via the CaMKII-dependent pathway in hypertensive cardiac hypertrophy.
Methods and Results: We used normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Whole cell membrane current was recorded in isolated ventricular myocyte by the patch-clamp method, and apamin-sensitive K+ current (IKAS), inhibited by apamin (100 nM), a blocker of SK channel, was evaluated. IKAS at 40 mV was present in SHR, whereas it was hardly detectable in WKY (0.579±0.046 pA/pF vs 0.022±0.062 pA/pF, both n=6, p<0.05). IKAS was almost completely abolished by 1 μM KN-93, an inhibitor of CaMKII, in SHR. Optical recordings of action potential in left ventricular anterior wall revealed that apamin prolonged the late phase of repolarization only in SHR (APD90 113.07±3.62 vs 124.95±3.62 msec, both n=4, p<0.05, and APD50 37.53±4.21 vs 50.48±4.21 msec, both n=4, p<0.05). Western blot analysis of SK channel protein isoform demonstrated that SK2 was significantly increased in SHR compared to WKY (SK2/GAPDH 0.66±0.07 vs 0.40±0.02, both n=6, p<0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHR (pCaMKII/GAPDH 0.80±0.06 vs 0.58±0.06, both n=6, p<0.05) despite comparable total amount of CaMKII between groups.
Conclusion: SK channels are upregulated via the enhanced activation of CaMKII in hypertensive cardiac hypertrophy.
Author Disclosures: K. Mizukami: None. H. Yokoshiki: None. H. Mitsuyama: None. M. Watanabe: None. T. Tenma: None. R. Kamada: None. S. Takada: None. H. Tsutsui: Research Grant; Significant; Tanabe-Mitsubishi, Daiichi-Sankyo, Takeda, Boehriner-Ingelheim, Bayer. Honoraria; Modest; Boehriner-Ingelheim, Bayer, BMS, Takeda. Honoraria; Significant; MSD, Tanabe-Mitsubishi, Daiichi-Sankyo, Teijin.
- © 2015 by American Heart Association, Inc.